The present invention relates to a novel imidazobezoquinone or a pharmacologically acceptable ester or salt thereof and a pharmaceutical composition for preventing or treating hypertension or congestive heart failure which contains the same as an active ingredient.
It is widely known that Renin-Angiotensin-Aldosterone system is closely connected with hypertensive pathogen or pathemia through control of blood pressure and amount of fluid or electrolyte. Prevention and treatment of hypertension (including essential hypertension) and further congestive heart failure by controlling this system have been studied for a long time. As the controlling methods, there are i) inhibition of synthesis or secretion of renin which is thought to be situated at the most upstream position, ii) inhibition of a reaction between renin and a substrate of renin (angiotensinogen) to decrease angiotensin (I) which is a reaction product, iii) inhibition of an enzyme which converts angiotensin (I) into angiotensin CID having strong vasoconstriction action, aldosterone secretion stimulating action, sympathetic nerve function promoting action and the like (angiotensin converting enzyme: ACE), iv) inhibition of the action of the produced angiotensin CID by blocking a receptor part thereof, v) activation of angiotensinase which rapidly degrades the produced angiotensin (II) and the like.
Among the agents active in this system, the study of ACE inhibitors is most advanced, and many such drugs are used for preventing or treating hypertension or congestive heart failure. However, since the ACE inhibitors are not selective and act toward other systems such as kalliklein-kinin system and the like, there is a clinical problem in that the side effects such as skin rash and dry cough occur more frequently. For this reason, many attempts to develop a renin inhibitor, which is thought to be more selective, have been tried, but have not successfully been marketed.
The putative peptide Angiotensin II antagonist Saralasin has been available for over 30 years. However, its therapeutic use has been severely limited by its partial agonistic action, short plasma half-life and lack of oral activity. Since the discovery of a "non-peptide" Angiotensin H antagonist by Takeda (Japan Kokai Patent 1979--148,788, 1981--71,073, 1982--98,270, 1983--157,768), extensive efforts have been made to modify or optimize this prototype lead especially by Dupont. These are reported in EP-A02533 10 and EP-A0291969, and the compound known as Dup753 is currently being clinically tested. The structure of Dup753 is set out below: ##STR2##
However, since this compound is usually produced as 1:1 positional isomer upon N-alkylation, Dup753 can not be selectively synthesized unless a special process is used, and this is thought to be a problem for mass production. On the other hand, it was thought to be effective at that time that the 5-position of the imidazole should have a polar group for increasing the pharmacological activity. This thinking was compelled to be significantly modified by the finding of benzimidazoles shown in EP-A0392317 (also reported in EP-A-0400835 and EP-A0399732 later). Further, this was developed into imidazopyridines (see EP-A0399731, EP-A0400974 and EP-A0415886). An example of such a structure is shown below: ##STR3##